Angioplasty procedures have dramatically increased as a treatment for occluded arteries. However, vessels often experience reclosure following the angioplasty procedure. The closure of vessels following angioplasty is known as restenosis. The process of restenosis can occur in over 30% of the cases, depending upon the vessel location, lesion length, as well as other variables.
Restenosis may be caused in some cases by simple mechanical reflex; e.g. caused by the elastic rebound of the arterial wall and/or by dissections in the vessel wall caused by the angioplasty procedure. These mechanical problems have been mitigated somewhat by the use of stents to hold open and prevent elastic rebound of the vessel, and reducing the level of restenosis for many patients. The stent is typically introduced by catheter into a vascular lumen and expanded into contact with the stenosed vascular lesion, thereby providing internal support for the vessel wall. Examples of stents, which have been used in the clinics include stents disclosed in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor which are incorporated herein by reference in their entirety.
Another aspect of restenosis is believed to be a natural healing reaction to the injury of the arterial wall that is caused by the angioplasty procedure. The final result of the complex steps of the healing process is intimal hyperplasia, the migration and proliferation of medial smooth muscle cells, until the vessel is again occluded.
Stents are typically tubular metallic devices, which are thin-metal screen-like scaffolds, and are inserted in a compressed form and then expanded at the target site. The stents are intended to provide long-term support for the expanded vessel, to keep it from restenosing over time. Unfortunately, initial data from the clinic indicates that the stent implants are not entirely successful in their mission, and in as many as 30% or more of the cases, the vessel restenoses within one year. It would be desirable to have medication(s) available on the stent surface to cope with problems, which arise on the stent surface or in adjacent patient tissue.
When coronary stents are placed, patients often are subjected to aggressive anti-thrombogenic, anti-platelet regimes in order to prevent thrombus formation on the stent surfaces. Thrombus formation on stent surfaces can be a natural consequence of placement of metal objects in the vasculature. It is recognized that the thrombi formed on stents may break loose from the stent, and produce undesired and dangerous occlusions elsewhere in the vasculature. Unfortunately, an aggressive anti-thrombogenic regime compromises a patient's ability to heal injuries that accompany the stenting procedure or other collateral procedures that may have been required. Thus, it is desirable that methods be found that reduce the need for the aggressive anti-thrombogenic therapy associated with coronary stent placement.
To address these problems, various approaches have been proposed. In EP 0 706 376 B1, Burt, et al, proposed that paclitaxel could be incorporated in polymeric layers. Examples included polycaprolactam, poly (lactic-co-glycolic acid), and others. However, many of these layers are biodegradable, and may thus depend upon the enzymatic composition of the patient. It is known that the enzymatic compositions vary considerably from patient to patient. It is thus likely that the biodegradation process and drug release rate would occur at different rates from patient to patient. Furthermore, the polymers used in this disclosure possess inferior adhesion for this application.
U.S. Pat. No. 5,837,008, Berg, et al., U.S. Pat. No. 5,851,217, Wolff, et al., U.S. Pat. No. 5,873,904, Ragheb, et al., and U.S. Pat. No. 6,344,035, Chudzik, et al., describe incorporation of drugs in multiple layers of a single polymer on stents, wherein the drug-polymer layers are applied in one or more consecutive applications. Polymers listed include bioabsorbable and biostable examples. Bioabsorbable examples listed include poly (L-lactic acid), poly(lactide-co-glycolide), and poly(hydroxybutyrate-co-valerate). Drugs listed include heparin and other anticoagulant agents, glucocorticoid or other anti-inflammatory agents, and various anti-replicate agents. Bioabsorbable polymers may depend on the enzymatic composition of the patient, and may be subject to patient to patient variation in drug release. Also, such polymers possess inferior adhesion for this application. Biostable polymers listed include silicone, polyurethanes, polyesters, vinyl homopolymers and copolymers, acrylate homopolymers and copolymers, polyethers, and cellulosics. Furthermore, the use of a single polymer in the drug release layer limits the drug release dynamics to that enabled by the specific polymer used in the layer, and is thus less able to regulate the drug release dynamics to the same extent as is possible using hybrid polymer layers. Further, optimizing drug release dynamics does not provide a coating with the necessary adhesion and flexibility to be clinically acceptable on a stent.
It has been proposed to provide stents, which are seeded with endothelial cells. In one experiment, sheep endothelial cells that had undergone retrovirus-mediated gene transfer for either bacterial beta-galactosidase or human tissue-type plasminogen activator were seeded onto stainless steel stents and grown until the stents were covered. The cells could therefore able to be delivered to the vascular wall where they could provide therapeutic proteins. Other methods of providing therapeutic substances to the vascular wall include simple heparin-coated metallic stents, whereby a heparin coating is ionically or covalently bonded to the stent.
U.S. Pat. No. 5,843,172 to Yan, describes a porous metallic stent in which medication is loaded into the pores of the metal. The stent may also have a polymeric cover, which would contain a different drug than the drug that was loaded into the metal pores. This has the ability to deliver more than one drug, but the ability to mediate the drug release dynamics is limited by the fact that only one type of polymer is used, and the drug in the metallic pores is not bound in a polymeric medium. It has been found that the use of pores without polymer entrapment of the drug results in the drug release rate/profile being entirely dependent on the drug solubility.
Finally, Von Bergelen et al. “The JOSTENT™ Coronary Stent Graft-Just Another Stent? . . . or How Should it be Implanted?”, Abstract: 825-4, ACC 2000/49th Annual Scientific Session, Mar. 12-15, 2000, Anaheim, Calif., USA, describes a sleeve of two stents with an ultra thin PTFE tube there between, which was implanted in 24 patients who had suffered acute coronary ruptures. This method mandates the use of oversized high-pressure balloon catheters to achieve adequate expansion of this new coronary stent graft (CSG). In addition, the endoprosthsesis must be accurately sized and placed to avoid occlusion of side branches originating from the target lesion segment, and thrombus formation is a concern.
Thus, there is a need for technology that can consistently provide therapeutic activity from the surfaces of stents in order to reduce the incidence of restenosis and thrombus formation after coronary stenting procedures in the clinic.